The main objective of this project is to improve our understanding of the hypoxia sensing by delineation of the molecular pathology of a congenital defect of this pathway that leads to a constitutive upregulation of the hypoxia sensing-Chuvash polycythemia (CP). Hypoxic sensing is an essential physiological mechanism that developed in mammals that control many important physiological and developmental processes including regulation of erythropoiesis. A gene that leads to a disease phenotype must be involved in an important, non-redundant physiological control point. Thus, the identification of the gene causing CP will improve our understanding of hypoxia sensing. The proposed research has the following specific aims: Aim 1) Define the phenotype of CP; Aim 2) Examine the in vitro growth of erythroid CP progenitors and elucidate the CP functional defect under intermittent hypoxic conditions; and Aim 3) Map and isolate the CP gene and determine its mutation(s) leading to CP phenotype.